title: A novel upregulation of glutathione peroxidase 1 by knockout of liver-regenerating protein Reg3β aggravates acetaminophen-induced hepatic protein nitration.
abstract: Murine regenerating islet-derived 3β (Reg3β) represents a homologue of human hepatocarcinoma-intestine-pancreas/pancreatic-associated protein and enhances mouse susceptibility to acetaminophen (APAP)-induced hepatotoxicity. Our objective was to determine if and how knockout of Reg3β (KO) affects APAP (300 mg/kg, ip)-mediated protein nitration in mouse liver. APAP injection produced greater levels of hepatic protein nitration in the KO than in the wild-type mice. Their elevated protein nitration was alleviated by a prior injection of recombinant mouse Reg3β protein and was associated with an accelerated depletion of the peroxynitrite (ONOO(-)) scavenger glutathione by an upregulated hepatic glutathione peroxidase-1 (GPX1) activity. The enhanced GPX1 production in the KO mice was mediated by an 85% rise (p<0.05) in the activity of selenocysteine lyase (Scly), a key enzyme that mobilizes Se for selenoprotein biosynthesis. Knockout of Reg3β enhanced AP-1 protein and its binding activity to the Scly gene promoter, upregulating its gene transcription. However, knockout of Reg3β did not affect gene expression of other key factors for selenoprotein biosynthesis. In conclusion, our findings unveil a new metabolic role for Reg3β in protein nitration and a new biosynthesis control of GPX1 by a completely "unrelated" regenerating protein, Reg3β, via transcriptional activation of Scly in coping with hepatic protein nitration. Linking selenoproteins to tissue regeneration will have profound implications in understanding the mechanism of Se functions and physiological coordination of tissue regeneration with intracellular redox control.
authors.affiliation: Department of Animal Science, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Jun-Won
authors.initials: JW
authors.lastname: Yun
authors.affiliation: Department of Animal Science, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Krystal
authors.initials: K
authors.lastname: Lum
authors.affiliation: Department of Animal Science, Cornell University, Ithaca, NY 14853, USA. Electronic address: XL20@cornell.edu.
authors.forename: Xin Gen
authors.initials: XG
authors.lastname: Lei
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D005979:Glutathione Peroxidase / Q000096:biosynthesis*; D008190:Lyases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D051140:Selenoproteins / Q000378:metabolism; D015854:Up-Regulation; D000094765:Glutathione Peroxidase GPX1
chemical_list: D018712:Analgesics, Non-Narcotic; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; C490253:Reg3b protein, mouse; D051140:Selenoproteins; D000082:Acetaminophen; D005979:Glutathione Peroxidase; D008190:Lyases; C034278:selenocysteine lyase; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse
keywords: ALT; AP-1; APAP; Akt; CYP2E1; Free radicals; GPX; GPX1; GR; GS; GSH; GSSG; GST; NF-1; PN; Protein nitration; Reg3β; SBP; SOD; SPS; Scly; SeP; SelK; Selenocysteine lyase; Selenoproteins; YY1; Yin Yang 1; acetaminophen; activator protein 1; alanine aminotransferase; cytochrome P450 2E1; glutathione; glutathione S-transferase; glutathione peroxidase; glutathione reductase; glutathione synthetase; iNOS; inducible NO synthase; intraperitoneal; ip; nuclear factor 1; oxidized glutathione; peroxynitrite; protein kinase B; regenerating islet-derived 3β; selenocysteine insertion sequence-binding protein; selenocysteine lyase; selenophosphate synthetase; selenoprotein K; selenoprotein P; superoxide dismutase; γ-GCS; γ-glutamylcysteine synthetase